SPP1 is associated with adverse prognosis and predicts immunotherapy efficacy in penile cancer.

BACKGROUND: The effect of SPP1 in squamous cell carcinoma of the penis (PSCC) remained unknown. We attempted to clarify the function of the SPP1 gene in PSCC. METHOD: Eight paired penile cancer specimens (including penile cancer tissue, paracancerous tissue, and positive lymph node tissue) subjected to whole transcriptome sequencing were analysed to identify differentially expressed genes. We used immunohistochemistry to detect the expression of SPP1 protein and immune cell related proteins in penile cancer tissue. Then, we performed weighted gene coexpression network analysis (WGCNA) to identify the genes related to SPP1 in penile cancer tissue and positive lymph node tissue. Based on the GSE57955 dataset, the CIBERSORT and ssGSEA algorithms were carried out to investigate the immune environment of PSCC. GSVA analysis was conducted to identify the signaling pathways related to SPP1 subgroups. Enzyme-linked immunosorbent assay (ELISA) method was adopted to detect SPP1 level in the serum of 60 patients with penile cancer. RESULTS: Differential analysis indicated that SPP1 was the most differentially upregulated gene in both penile cancer tissues and positive lymph node tissues. Survival analysis suggested that the prognosis of the low-SPP1 group was significantly poorer than that of the high-SPP1 group. Subsequently, immune-related bioinformatics showed that SPP1 was significantly associated with B cells, CD8 + T cells, CD4 + T cells, macrophages, helper T cells, neutrophils and dendritic cells. The immunohistochemical results showed that the high-SPP1 group was characterized by relatively high expression of CD16 and relatively low expression of CD4. GSVA analysis indicated that high-SPP1 group was significantly associated with immune-related pathways such as PD-L1 expression and the PD-1 checkpoint pathway in cancer and the TNF signaling pathway. ELISA demonstrated that the serum level of SPP1 in patients with positive lymph node metastasis of penile cancer was significantly higher than that in patients with negative lymph node metastasis of penile cancer. CONCLUSION: Our study shows that the SPP1 gene might be an effective biomarker for predicting the prognosis and the efficacy of immunotherapy in PSCC patients.

Effects of status of lymph vascular invasion on the survival of patients with squamous cell carcinoma of the penis / 现代泌尿外科杂志

【Objective】 To explore the effects of status of lymph vascular invasion (LVI) on the survival of patients with squamous cell carcinoma of the penis (SCCP). 【Methods】 Data of patients diagnosed as SCCP during Jan.1, 2010 and Dec.31, 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier method was used to draw the survival curve of patients with different LVI statuses, and log-rank test was conducted in parallel. Univariate and multivariate Cox regression analyses were used to assess the effects of LVI status on the overall survival. Patients were divided into different subgroups based on stage (localized, regional, and distant metastasis) and grade (well, moderately and poorly differentiated) of tumor, and the effects of LVI status on the overall survival of patients in different subgroups were assessed. 【Results】 A total of 1 435 patients were involved, including 1 102 (76.8%) without LVI and 333 (23.2%) with LVI. Median survival time of patients without LVI and with LVI were 27.5 months and 17.0 months, respectively (χ2=55.028, P<0.001). Cox regression analyses showed LVI was a significant prognostic factor in SCCP patients (HR=1.280, 95%CI:1.044-1.569, P=0.018). In the subgroup analysis, LVI was an independent risk factor affecting the overall survival of patients with localized tumor (HR=1.446, 95%CI:1.009-2.110, P=0.046) and regional tumor (HR=1.323, 95%CI:1.018-1.720, P=0.036);it was also an independent risk factor affecting the overall survival of SCCP patients with well differentiated tumor (HR=2.797, 95%CI:1.573-4.971, P=0.046) and moderately differentiated tumor (HR=1.431, 95%CI:1.071-1.914, P=0.015). 【Conclusion】 LVI status is a significant factor affecting the prognosis of SCCP patients. LVI is an independent risk factor for the overall survival of SCCP patients with localized and regional tumor, moderately differentiated and well differentiated tumor.

Primary Penile Squamous Cell Cancer-Related Malignant Priapism in a Cystectomized Patient: A Case Report.

Priapism is one of the most common urologic emergencies and is characterized by a prolonged and painful erectile state unrelated to sexual stimulation or sexual desire. Neoplasm-associated priapism is a rare condition and is usually caused by corporeal metastases of other pelvic area malignancies. Primary penile malignancy-related malignant priapism is extremely rare. In this reported case, an 82-year-old male presented with priapism. The penile doppler ultrasound and pelvic magnetic resonance imaging were compatible with ischemic priapism and corporal mass. Subsequently, the patient underwent total penectomy and bilateral superficial inguinal lymphadenectomy. The pathology report was consistent with primary penile squamous cell cancer (SCC), so the patient underwent adjuvant radiotherapy. However, he developed multiple metastases and could survive for about six months. The patient had undergone radical cystectomy (RC) and urethrectomy 19 and 2 years ago due to urothelial carcinoma, respectively. To the best of our knowledge, this is the second case of malignant priapism due to primary penile SCC and represents one of the longest urethral recurrence periods after RC. When a patient presents with malignant priapism, primary penile malignancies should be considered in differential diagnosis, even if the patient has a history of pelvic area malignancies.

Updates in the use of radiotherapy in the management of primary and locally-advanced penile cancer.

Objective: Penile cancer is a rare malignancy in most developed countries, but may represent a significant oncologic challenge in certain African, Asian, and South American regions. Various treatment approaches have been described in penile cancer, including radiotherapy. This review aimed to provide a synopsis of radiotherapy use in penile cancer management and the associated toxicities. In addition, we aimed to discuss palliative radiation for metastases to the penis and provide a brief overview of how tumor biology may assist with treatment decision-making. Methods: Peer-reviewed manuscripts related to the treatment of penile cancer with radiotherapy were evaluated by a PubMed search (1960-2021) in order to assess its role in the definitive and adjuvant settings. Selected manuscripts were also evaluated for descriptions of radiation-related toxicity. Results: Though surgical resection of the primary is an excellent option for tumor control, select patients may be treated with organ-sparing radiotherapy by either external beam radiation or brachytherapy. Data from randomized controlled trials comparing radiotherapy and surgery are lacking, and thus management is frequently determined by institutional practice patterns and available expertise. Similarly, this lack of clinical trial data leads to divergence in opinion regarding lymph node management. This is further complicated in that many cited studies evaluating lymph node radiotherapy used non-modern radiotherapy delivery techniques. Groin toxicity from either surgery or radiotherapy remains a challenging problem and further risk assessment is needed to guide intensification with multi-modal therapy. Intrinsic differences in tumor biology, based on human papillomavirus infection, may help aid future prognostic and predictive models in patient risk stratification or treatment approach. Conclusion: Penile cancer is a rare disease with limited clinical trial data driving the majority of treatment decisions. As a result, the goal of management is to effectively treat the disease while balancing the importance of quality of life through integrated multidisciplinary discussions. More international collaborations and interrogations of penile cancer biology are needed to better understand this disease and improve patient outcomes.

A Case Report on Advanced Squamous Cell Carcinoma of the Penis.

This is a case of a 60-year-old Hispanic male with a history of poorly controlled diabetes who presented to the hospital with a chief complaint of a mass in the penis with mucopurulent discharge and drainage. The patient reported that the mass has been present for one year and had increased in size over the past six months. The patient had the mass biopsied at an outside surgical center one year ago, which was supposedly negative for cancer. On the initial physical examination, there was a large exophytic necrotic mass entirely replacing the penis with complete obliteration of the normal architecture of the glans and phallus with foul, purulent discharge. Significant bilateral palpable inguinal lymphadenopathy was present. A bedside biopsy was performed, which revealed squamous cell carcinoma (SCC). Computed tomography (CT) of the chest, abdomen, and pelvis was ordered for staging and revealed extensive pulmonary and hepatic metastasis, as well as bulky inguinal and retroperitoneal lymph node involvement. Systemic chemotherapy was offered to the patient; however, the patient declined and opted for hospice.

Tumor Location May Independently Predict Survival in Patients With M0 Squamous Cell Carcinoma of the Penis.

Background: To determine the association between tumor location and both clinicopathological characteristics and the survival of patients with M0 squamous cell carcinoma of the penis (SCCP). Methods: Data of 455 patients diagnosed with M0 SCCP between 1975 and 2018 were collected from the Surveillance, Epidemiology, and End Results (SEER) database of the United States National Cancer Institute. The effects of tumor location on overall survival (OS) and penile carcinoma-specific survival (PCSS) were analyzed using the Kaplan-Meier method. The Cox proportional hazards regression model was used to determine the impact of tumor location on PCSS. Results: SCCP was more likely to occur in the prepuce or glans (90%). Although no significant difference was observed between the OS of patients with M0 SCCP in the prepuce or glans and those with M0 SCCP in the body of the penis (p = 0.307), the former had better PCSS (p = 0.024). Moreover, M0 SCCP in the prepuce or glans was also significantly associated with better PCSS in patients with advanced age (age ≥ 60 years, p = 0.011), other ethnicities (p = 0.003), T2-T4 stage (p = 0.036), larger tumors (≥3 cm, p = 0.001), no regional lymph nodes removed (p = 0.044), and radical surgery (p = 0.027). Multivariate analysis confirmed that tumor location is an independent prognostic factor for patients with M0 SCCP [hazard ratio (HR) 1.881, p = 0.026]. Conclusions: Tumor location is an independent prognostic factor for patients with M0 SCCP, and tumors in the prepuce or glans portend better PCSS.

Adherence to European Association of Urology and National Comprehensive Cancer Network Guidelines Criteria for Inguinal and Pelvic Lymph Node Dissection in Penile Cancer Patients-A Survey Assessment in German-speaking Countries on Behalf of the European Prospective Penile Cancer Study Group.

BACKGROUND: Urologists' adherence to European Association of Urology and National Comprehensive Cancer Network guideline recommendations to perform inguinal (ILND) and pelvic (PLND) lymph node dissection in penile cancer (PC) patients is not known. OBJECTIVE: To assess a German-speaking European cohort of urologists based on their criteria to perform ILND and PLND in PC patients. DESIGN, SETTING, AND PARTICIPANTS: A 14-item survey addressing general issues of PC treatment was developed and sent to 45 clinical centers in Germany (n = 34), Austria (n = 8), Switzerland (n = 2), and Italy (n = 1). INTERVENTION: Two of the 14 questions assessed the criteria to perform ILND and ipsilateral PLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Correct responses for ILND and PLND criteria were assessed. Based on a multivariate logistic-regression-model, criteria independently predicting guideline adherence were identified. RESULTS AND LIMITATIONS: In total, 557 urologists participated in the survey, of whom 43.5%, 19.3%, and 37.2% were residents in training, certified, and in leading positions, respectively. ILND and PLND criteria were correctly identified by 35.2% and 23.9%, respectively. Of the participants, 23.3% used external sources for survey completion. The use of auxiliary tools (odds ratio [OR] 1.57; p[bootstrapped] = 0.028) and participants outside of Germany (OR 0.56; p[bootstrapped] = 0.006) were predictors of ILND guideline adherence. The number of PC patients treated yearly (p = 0.012; OR 1.06) and the use of auxiliary tools (p < 0.001; OR 5.88) were predictors of PLND adherence. Department size, healthcare status, professional status, and responsibility for PC surgery did not predict endpoints. Limitations include sample size and results in comparison with retrospective studies. CONCLUSIONS: Our results demonstrate overall suboptimal knowledge of the correct indications to perform ILND and PLND in PC patients among the surveyed urologists. We propose that governments and healthcare providers should be encouraged to centralize PC management. PATIENT SUMMARY: The management of inguinal and pelvic lymph nodes is crucial for the survival of penile cancer patients. Disease rarity mandates referral to clinical practice guidelines for appropriate treatment selection.

The prognostic significance of primary tumor size in squamous cell carcinoma of the penis.

BACKGROUND: To evaluate the association of primary tumor size with clinicopathologic characteristics and survival of patients with squamous cell carcinoma of the penis (SCCP). METHODS: This study analyzed the data of 1001 patients with SCCP, obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2014. The Kaplan-Meier method and the Cox proportional hazards regression model were used to analyze the effects of primary tumor size on overall survival (OS) and penile carcinoma-specific survival (PCSS). RESULTS: Advanced T stage (P < 0.001), lymph node metastasis (P < 0.001) and distant metastasis (P = 0.001) were more frequently associated with SCCP patients with tumor size ≥ 3 cm than those with tumor size < 3 cm. In Kaplan-Meier analyses, the patients with large tumors (≥ 3 cm) exhibited an inferior OS and PCSS than those with small tumors (< 3 cm). Moreover, tumor size was identified to be an independent prognostic factor for OS [hazard ratio (HR) 1.665, P < 0.001] and PCSS (HR 2.076, P = 0.003) of patients with SCCP in multivariate analyses. CONCLUSIONS: Large tumor size is associated with adverse clinicopathological characteristics of patients with SCCP. Besides, tumor size represents an independent prognostic factor for OS and PCSS. Therefore, clinical assessment of tumor size as a crucial prognostic factor might be highly beneficial for early intervention in patients with SCCP.

Long-term multicentre experience of adjuvant radiotherapy for pN3 squamous cell carcinoma of the penis.

OBJECTIVE: To present the long-term adjuvant radiotherapy outcomes of patients with pN3 squamous cell carcinoma of the penis (SCCp) treated at two UK centres. PATIENTS AND METHODS: We conducted a retrospective audit of all pN3 SCCp patients, deemed suitable for adjuvant therapy by a specialist multidisciplinary team at St George's and Leeds Hospitals, who received adjuvant radiotherapy. Primary outcomes were recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Secondary outcomes were time to adjuvant treatment, frequency of in-field recurrence, site and side of recurrence, and dose and schedule of radiotherapy. RESULTS: A total of 146 patients were included: 121 completed radiotherapy, 4 did not complete radiotherapy and 21 did not start it. The median (interquartile range [IQR]) age was 59 (54-70)years. The 5-year RFS was 51%, CSS was 51% and OS was 44%. Adjuvant radiotherapy was started at a median (IQR) of 75 (48-106) days. A dose of 45 Gy in 20 fractions was most commonly used. Of the 125 patients who started adjuvant treatment, 55 relapsed. Of these relapses, 30 occurred in an inguinal or pelvic nodal station and 26 of the 30 were in a radiation field. Relapses in 18 of the 55 cases were in visceral sites only and seven were in both nodal (non-irradiated sites) and visceral sites. Doses of <50 Gy were used more commonly before 2013 and higher doses (>50 Gy) were more commonly used after 2013. CONCLUSIONS: Application of a standard radiotherapy protocol within a centralized supra-network setting has achieved survival outcomes that would appear better than those previously documented for either radiotherapy or chemotherapy in a cohort with solely pN3 disease. The addition of adjuvant chemotherapy may improve these outcomes further. These data suggest that adjuvant radiotherapy has a role to play in the management of men with pN3 SCCp.

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer.

The incidence of penile cancer (PeCa) is increasing worldwide, however, the highest rates are reported in underdeveloped countries. The molecular mechanisms that underly the onset and progression of these tumors are still unclear. Therefore, our goal was to determine the genome-wide copy number alterations and the involvement of human papiloma virus (HPV) (TP53 and RB1), inflammatory (COX2 and EGFR), and PI3K/AKT pathway (AKT1, AKT2, EGFR, ERBB3, ERBB4, PIK3CA, and PTEN) associated genes in patients with PeCa from a high incidence region in Brazil (Maranhão). HPV genotyping was performed by nest-PCR and genome sequencing, copy number alterations (CNAs) by array comparative genomic hybridization and gene copy number status, gene, and protein expression by quantitative polymerase chain reaction, reverse transcriptase-quantitative polymerase chain reaction, and immunohistochemistry, respectively. HPV genotyping revealed one of the highest frequencies of HPV reported in PeCa, affecting 96.4% of the cases. The most common CNAs observed were located at the HPV integration sites, such as 2p12-p11.2 and 14q32.33, where ADAM 6, KIAA0125, LINC00226, LINC00221, and miR7641-2, are mapped. Increased copy number of ERBB3 and EGFR genes were observed in association with COX2 and EGFR overexpression, reinforcing the role of the inflammatory pathway in PeCa, and suggesting anti-EGFR and anti-COX2 inhibitors as promising therapies for PeCa. Additionally, TP53 and RB1 messenger RNA downregulation was observed, suggesting the occurrence of other mechanisms for repression of these oncoproteins, in addition to the canonical HPV/TP53/RB1 signaling pathway. Our data reinforce the role of epigenetic events in abnormal gene expression in HPV-associated carcinomas and suggest the pivotal role of HPV driving CNAs and controlling gene expression in PeCa.

Prognostic value of lymphovascular invasion in patients with squamous cell carcinoma of the penis following surgery.

BACKGROUND: To evaluate the prognostic value of Lymphovascular Invasion (LVI) in patients with squamous cell carcinoma of the penis (SCCP) following surgery. PATIENTS AND METHODS: This retrospective study analyzed the data of 891 eligible patients with SCCP who were diagnosed between 2010 and 2014, obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The patients were categorized by LVI, age, grade, T stage, lymph nodes status, distant metastasis, regional lymph nodes removed, and surgery. Overall survival (OS) and penile carcinoma-specific survival (PCSS) were evaluated by Kaplan-Meier method and Cox proportional hazards regression model. RESULTS: The presence of LVI was significantly associated with increased risk of advanced T stage, high grade, lymph node metastasis, and distant metastasis (P < 0.001 for all). In Kaplan-Meier analyses, patients with the presence of LVI had significantly lower OS and PCSS than those with the absence of LVI (P < 0.001 for both,). The presence of LVI was also significantly associated with poorer OS and worse PCSS in patients with Tx + Ta + T1 stage (P = 0.007, P < 0.001), N0 stage (P < 0.001, P = 0.040), grade 1 (P = 0.001, P < 0.001), grade 2 (P = 0.001, P = 0.014), no distant metastasis (P < 0.001 for both), no regional lymph nodes removed (P < 0.001 for both), Non-radical surgery (P < 0.001 for both) and radical surgery(P = 0.037, P = 0.002). In multivariate analyses, the presence of LVI in patients with SCCP following surgery was found to be a significant independent predictor of decreased OS (hazard ratio 1.403, P = 0.039). CONCLUSIONS: The LVI status might be a crucial prognostic indicator for overall survival in patients with SCCP.

National Trends and Predictors of Locally Advanced Penile Cancer in the United States (1998-2012).

BACKGROUND: We analyzed the trends in presentation of squamous cell carcinoma (SCC) of the penis and determined the socioeconomic predictors for locally advanced (cT3-cT4) disease in the United States. PATIENT AND METHODS: The National Cancer Database was queried for patients with clinically nonmetastatic penile SCC and staging available from 1998 to 2012. Temporal trends per tumor stage were evaluated, and a multivariable logistic regression model was used to identify predictors for advanced presentation during the study period. RESULTS: A total of 5767 patients with stage ≤ T1-T2 (n = 5423) and T3-T4 (n = 344) disease were identified. Increasing trends were noted in all stages of penile SCC with a greater proportion of advanced cases over time (P = .001). Significant predictors of advanced presentation were age > 55 years, the presence of comorbidities, and Medicaid or no insurance (P < .05 for all). CONCLUSION: More penile SCC is being detected in the United States. Our results have demonstrated older age, presence of comorbidities, and Medicaid or no insurance as potential barriers to early access of care in the male population. Understanding the current socioeconomic gaps could help guide targeted interventions in vulnerable populations.

The Danish National Penile Cancer Quality database.

AIM OF DATABASE: The Danish National Penile Cancer Quality database (DaPeCa-data) aims to improve the quality of cancer care and monitor the diagnosis, staging, and treatment of all incident penile cancer cases in Denmark. The aim is to assure referral practice, guideline adherence, and treatment and development of the database in order to enhance research opportunities and increase knowledge and survival outcomes of penile cancer. STUDY POPULATION: The DaPeCa-data registers all patients with newly diagnosed invasive squamous cell carcinoma of the penis in Denmark since June 2011. MAIN VARIABLES: Data are systematically registered at the time of diagnosis by a combination of automated data-linkage to the central registries as well as online registration by treating clinicians. The main variables registered relate to disease prognosis and treatment morbidity and include the presence of risk factors (phimosis, lichen sclerosus, and human papillomavirus), date of diagnosis, date of treatment decision, date of beginning of treatment, type of treatment, treating hospital, type and time of complications, date of recurrence, date of death, and cause of death. DESCRIPTIVE DATA: Registration of these variables correlated to the unique Danish ten-digit civil registration number enables characterization of the cohort, individual patients, and patient groups with respect to age; 1-, 3-, and 5-year disease-specific and overall survival; recurrence patterns; and morbidity profile related to treatment modality. As of August 2015, more than 200 patients are registered with ∼65 new entries per year. CONCLUSION: The DaPeCa-data has potential to provide meaningful, timely, and clinically relevant quality data for quality maintenance, development, and research purposes.

DaPeCa-2: Implementation of fast-track clinical pathways for penile cancer shortens waiting time and accelerates the diagnostic process--A comparative before-and-after study in a tertiary referral centre in Denmark.

OBJECTIVE: The aim of this study was to examine the feasibility and impact of a fast-track referral pathway on clinical time intervals in penile cancer. MATERIALS AND METHODS: This observational study from a tertiary referral centre included 263 patients diagnosed before and after the introduction of an intervention to reduce clinical time intervals, the Cancer Patient Pathway (CPP). The CPP included fast-track referral and set time-frames for units participating in cancer diagnosis and treatment, and was introduced for penile cancer in Denmark on 1 January 2009. Median time intervals (in calendar days) with interquartile range were the main outcome measure. RESULTS: A trend towards reduction was observed in all clinical time intervals, with a statistically significant reduction in the system interval (p = 0.01) and tertiary centre interval (p < 0.0001). The proportion of patients treated within the maximum accepted time-frame of 37 days after referral steadily increased after implementation of the CPP. In particular, unjustified waiting time was reduced significantly. This was mainly achieved through pre-booking of appointments and diagnostic time slots by a dedicated clinical coordinator. CONCLUSIONS: To the authors' knowledge, this is the first study examining the feasibility and impact of an intervention to reduce clinical time intervals in penile cancer. The Danish CPP was successful in reducing system and tertiary centre intervals. Future interventions need to address the long patient interval. Longer follow-up is needed to study the impact of CPP on mortality.

DaPeCa-2: Implementation of fast-track clinical pathways for penile cancer shortens waiting time and accelerates the diagnostic process--A comparative before-and-after study in a tertiary referral centre in Denmark.

OBJECTIVE: The aim of this study was to examine the feasibility and impact of a fast-track referral pathway on clinical time intervals in penile cancer. MATERIALS AND METHODS: This observational study from a tertiary referral centre included 263 patients diagnosed before and after the introduction of an intervention to reduce clinical time intervals, the Cancer Patient Pathway (CPP). The CPP included fast-track referral and set time-frames for units participating in cancer diagnosis and treatment, and was introduced for penile cancer in Denmark on 1 January 2009. Median time intervals (in calendar days) with interquartile range were the main outcome measure. RESULTS: A trend towards reduction was observed in all clinical time intervals, with a statistically significant reduction in the system interval (p = 0.01) and tertiary centre interval (p < 0.0001). The proportion of patients treated within the maximum accepted time-frame of 37 days after referral steadily increased after implementation of the CPP. In particular, unjustified waiting time was reduced significantly. This was mainly achieved through pre-booking of appointments and diagnostic time slots by a dedicated clinical coordinator. CONCLUSIONS: To the authors' knowledge, this is the first study examining the feasibility and impact of an intervention to reduce clinical time intervals in penile cancer. The Danish CPP was successful in reducing system and tertiary centre intervals. Future interventions need to address the long patient interval. Longer follow-up is needed to study the impact of CPP on mortality.

DaPeCa-1: diagnostic accuracy of sentinel lymph node biopsy in 222 patients with penile cancer at four tertiary referral centres - a national study from Denmark.

OBJECTIVES: To estimate the diagnostic accuracy of sentinel lymph node biopsy (SNB) in patients with penile cancer and assess SNB complications in a national multicentre setting. PATIENTS AND METHODS: Retrospectively data were collected from records in four university centres by one medical doctor covering all SNBs performed in Denmark between 1 January 2000 and 31 December 2010. Patients had either impalpable lymph nodes (LNs) in one or both groins, or had a palpable inguinal mass from which aspiration cytology failed to reveal malignancy. Patients were injected with nanocolloid technetium and had a scintigram recorded before the SNB. The primary endpoint was LN recurrence on follow-up. The secondary endpoint was complications after SNB. Diagnostic accuracy was computed. RESULTS: In all, 409 groins in 222 patients were examined by SNB. The median (interquartile range) follow-up of patients who survived was 6.6 (5-10) years. Of 343 negative groins, eight were false negatives. The sensitivity was 89.2% (95% confidence interval 79.8-95.2%) per groin. Interestingly, four of 67 T1G1 patients had a positive SNB. In all, 28 of 222 (13%) patients had complications of Clavien-Dindo grade I-IIIa. CONCLUSION: Penile cancer SNB with a close follow-up stages LN involvement reliably and has few complications in a national multicentre setting. Inguinal LN dissection was avoided in 76% of patients.

A switch from epithelial to mesenchymal properties correlates with lymphovascular invasion in squamous cell carcinoma of the penis.

The purpose of the study was to assess the incidence and prognostic role of epithelial-to-mesenchymal-transition (EMT) in squamous cell carcinoma of the penis (SCCP). Sixty tumor specimens of surgically treated SCCP patients characterized by a central histopathologic review were stained with antibodies against E-cadherin, N-cadherin, ß-catenin, and vimentin. Staining profiles were scored by two independent raters, and correlated with pertinent clinical and pathological parameters and cancer-specific mortality (CSM; median follow-up: 34 months, interquartile range: 6-60 months). Correlation statistics proved good interobserver agreement in staining evaluation (K-values between 0.62 and 1.00, all p<0.001). Based on consensus decision between both raters, 36 study cases (60%) showed a switch from E-cadherin to N-cadherin (as a hallmark of EMT), which correlated with the presence of lymphovascular invasion (ρ=0.287, p=0.026) while failing to interfere with CSM. Although cadherin switch was correlated with a loss of membranous ß-catenin expression (ρ=0.629, p<0.001), none of the study cases showed nuclear ß-catenin expression, and only three EMT cases (8.3%) had tumor buds revealing vimentin expression. Our data suggest that roughly half of surgically treated SCCP cases exhibit EMT, a parameter correlating with lymphovascular invasion. However, further studies are clearly needed to validate the so far unresolved possible role of cadherin switch in terms of predicting nodal spread in patients with SCCP. Moreover, the apparently complex mechanisms driving EMT in SCCP should be explored by future studies, as knowledge about these might provide a so far unexploited basis for the development of novel targeted therapies against SCCP with metastatic dissemination.

Development and external validation of a prognostic tool for prediction of cancer-specific mortality after complete loco-regional pathological staging for squamous cell carcinoma of the penis.

OBJECTIVE: To develop a novel postoperative prognostic tool, which attempts to integrate both pathological tumour stage and histopathological factors, for prediction of cancer-specific mortality (CSM) of squamous cell carcinoma of the penis (SCCP). PATIENTS AND METHODS: Patients with SCCP treated with inguinal lymph node dissection (ILND) or sentinel LN biopsy at a single institution were used for nomogram development and internal validation (n = 434), while a second cohort was used for external validation (n = 338). Multivariable Cox proportional hazards were used to examine the prognostic ability of patient age, a modified tumour staging that distinguishes between spongiosum and cavernosum body ingrowth tumours, a modified LN staging that integrates information on presence/absence of LN metastasis, extent of inguinal LN metastases, pelvic LN involvement, and extranodal involvement, and tumour grade. Model performance was quantified using measures of discrimination and calibration. RESULTS: Overall, 36% of patients had positive LN metastases (n = 156). In univariable analyses, the modified tumour and LN staging systems were statistically significantly associated with CSM, and remained in the final model with a discrimination of 89% within internal validation, and 95% within external validation. Calibration was nearly perfect. CONCLUSIONS: The newly developed model integrates important prognostic factors, which existing models do not consider. Its performance was highly accurate using measures of discrimination and calibration.

Neoadjuvant taxane-based combination chemotherapy in patients with advanced penile cancer.

INTRODUCTION/BACKGROUND: Neoadjuvant taxane-based combination chemotherapy has shown promising results in unresectable squamous cell carcinoma of the head and neck area, and the penis. Our primary aim was to assess the objective response in penile cancer patients neoadjuvantly treated with taxane-based combination chemotherapy. Secondary outcomes were progression-free survival (PFS), disease-specific survival (DSS), and toxicity. PATIENTS AND METHODS: Twenty-six patients were treated within the framework of a nonrandomized institutional registration study with 4 courses of TPF (docetaxel, cisplatin, and 5-fluorouracil) for advanced penile cancer between 2008 and 2012. Response was measured using computed tomography (CT) and/or fluorodeoxyglucose positron emission tomography/CT according to Response Evaluation Criteria in Solid Tumours 1.1 criteria and European Organisation for Research and Treatment of Cancer recommendations, respectively. Toxicity, PFS, and DSS were analyzed using either the Common Toxicity Criteria of Adverse Events version 4.0 or the Kaplan-Meier methods. To analyze possible association with survival, univariable and multivariable Cox regression analyses were performed for tumor differentiation, N-category, recurrent disease, tumor margins, and administration of radiotherapy. RESULTS: During a median follow-up of 30 months, an imaging-based response was obtained in 60% (95% confidence interval [CI], 39%-79%) (15/25) of patients. However, pathologic complete response was observed in 1 of 25 evaluable patients (4%; 95% CI, 0%-20%). Toxicity was considerable with registered toxicity in every patient. The 2-year PFS and DSS probability were 12% and 28%, respectively. Patients responsive to chemotherapy had significantly better survival than nonresponsive patients. CONCLUSION: Despite a fairly good response percentage, TPF chemotherapy was poorly tolerated with disappointing survival rates. Therefore, other treatment options should be considered.